Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, 3C584 CG Utrecht, The Netherlands.
Division of Clinical Medicine, School of Medicine and Population Health, University of Sheffield, Sheffield S10 2TN, UK.
Mol Metab. 2023 Dec;78:101829. doi: 10.1016/j.molmet.2023.101829. Epub 2023 Oct 30.
In vivo studies in humans and mice have implicated the pseudokinase Tribbles 3 (TRIB3) in various aspects of energy metabolism. Whilst cell-based studies indicate a role for TRIB3 in adipocyte differentiation and function, it is unclear if and how these cellular functions may contribute to overall metabolic health.
We investigated the metabolic phenotype of whole-body Trib3 knockout (Trib3) mice, focusing on adipocyte and adipose tissue functions. In addition, we combined lipidomics, transcriptomics, interactomics and phosphoproteomics analyses to elucidate cell-intrinsic functions of TRIB3 in pre- and mature adipocytes.
Trib3 mice display increased adiposity, but their insulin sensitivity remains unaltered. Trib3 adipocytes are smaller and display higher Proliferating Cell Nuclear Antigen (PCNA) levels, indicating potential alterations in either i) proliferation-differentiation balance, ii) impaired expansion after cell division, or iii) an altered balance between lipid storage and release, or a combination thereof. Lipidome analyses suggest TRIB3 involvement in the latter two processes, as triglyceride storage is reduced and membrane composition, which can restrain cellular expansion, is altered. Integrated interactome, phosphoproteome and transcriptome analyses support a role for TRIB3 in all three cellular processes through multiple cellular pathways, including Mitogen Activated Protein Kinase- (MAPK/ERK), Protein Kinase A (PKA)-mediated signaling and Transcription Factor 7 like 2 (TCF7L2) and Beta Catenin-mediated gene expression.
Our findings support TRIB3 playing multiple distinct regulatory roles in the cytoplasm, nucleus and mitochondria, ultimately controlling adipose tissue homeostasis, rather than affecting a single cellular pathway.
在人类和小鼠的体内研究表明，假激酶 Tribbles 3（TRIB3）在能量代谢的各个方面都有牵连。虽然基于细胞的研究表明 TRIB3 在脂肪细胞分化和功能中起作用，但尚不清楚这些细胞功能是否以及如何有助于整体代谢健康。
我们研究了全身性 Trib3 敲除（Trib3）小鼠的代谢表型，重点研究脂肪细胞和脂肪组织的功能。此外，我们结合脂质组学、转录组学、相互作用组学和磷酸化蛋白质组学分析，阐明 TRIB3 在预成熟和成熟脂肪细胞中的细胞内功能。
TRIB3 小鼠表现出增加的肥胖，但它们的胰岛素敏感性保持不变。TRIB3 脂肪细胞较小，增殖细胞核抗原（PCNA）水平较高，表明在 i）增殖-分化平衡、ii）细胞分裂后扩张受损，或 iii）脂质储存和释放之间的平衡或其组合方面可能存在改变。脂质组学分析表明 TRIB3 参与后两个过程，因为甘油三酯储存减少，膜组成改变，这可以限制细胞扩张。综合相互作用组、磷酸化蛋白质组和转录组分析支持 TRIB3 通过多种细胞途径，包括有丝分裂原激活蛋白激酶（MAPK/ERK）、蛋白激酶 A（PKA）介导的信号转导以及转录因子 7 样 2（TCF7L2）和 Beta 连环蛋白介导的基因表达，在所有三个细胞过程中发挥作用。
我们的发现支持 TRIB3 在细胞质、核和线粒体中发挥多种不同的调节作用，最终控制脂肪组织稳态，而不是影响单一的细胞途径。
